Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lympoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

自闭症谱系障碍 （ASD） 代表了以临床和遗传异质性为特征的神经和发育障碍的复杂体。虽然 ASD 的病因尚不清楚，但发现许多 ASD 风险因素集中在细胞稳态所必需的细胞内质量控制机制上，包括自噬-溶酶体降解途径。研究报道了 ASD 人脑中的自噬受损以及脑自噬缺陷小鼠模型中的 ASD 样突触病理和行为，强调了自噬缺陷在 ASD 发病机制中的重要作用。为了确定大脑中改变的自噬是否也可能发生在可能提供有用生物标志物的外周细胞中，我们评估了 ASD 和对照受试者淋巴母细胞中的自噬活性。我们发现，由于自噬诱导受损，一部分 ASD 参与者的淋巴母细胞自噬受损。在 ASD 个体的死后人脑以及综合征 ASD 小鼠模型的大脑和外周血单核细胞中检测到类似的自噬变化。值得注意的是，我们发现 ASD 参与者的自噬受损与智力障碍之间存在很强的相关性。通过消耗不同脑细胞的关键自噬基因 Atg7，我们提供了进一步的证据，证明自噬缺陷会导致小鼠认知障碍。总之，我们的研究结果表明，自噬功能障碍是一种收敛机制，可以在自闭症个体子集的外周血细胞中检测到，并且淋巴母细胞自噬可以作为对 ASD 患者进行分层以开发靶向干预措施的生物标志物。